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1.
J Cyst Fibros ; 17(5): 607-615, 2018 09.
Article in English | MEDLINE | ID: mdl-29233471

ABSTRACT

BACKGROUND: Cystic Fibrosis (CF) lung disease is characterised by dysregulated ion transport that promotes chronic bacterial infection and inflammation. The impact of the specialised pro-resolution mediator resolvin D1 (RvD1) on airway surface liquid (ASL) dynamics and innate defence had not yet been investigated in CF airways. METHODS: Ex vivo studies were performed on primary cultures of alveolar macrophages and bronchial epithelial cells from children with CF and in human bronchial epithelial cell lines; in vivo studies were performed in homozygous F508del-CFTR mice treated with vehicle control or RvD1 (1-100nM). RESULTS: RvD1 increased the CF ASL height in human bronchial epithelium and restored the nasal trans-epithelial potential difference in CF mice by decreasing the amiloride-sensitive Na+ absorption and stimulating CFTR-independent Cl- secretion. RvD1 decreased TNFα induced IL-8 secretion and enhanced the phagocytic and bacterial killing capacity of human CF alveolar macrophages. CONCLUSION: RvD1 resolves CF airway pathogenesis and has therapeutic potential in CF lung disease.


Subject(s)
Cystic Fibrosis/drug therapy , Cystic Fibrosis/immunology , Docosahexaenoic Acids/pharmacology , Animals , Cell Line , Cells, Cultured , Child , Epithelial Cells/drug effects , Humans , Inflammation/drug therapy , Ion Transport/drug effects , Macrophages, Alveolar/drug effects , Mice
2.
Eur Respir J ; 44(2): 394-404, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24696116

ABSTRACT

Airway disease in cystic fibrosis (CF) is characterised by impaired mucociliary clearance, persistent bacterial infection and neutrophilic inflammation. Lipoxin A4 (LXA4) initiates the active resolution of inflammation and promotes airway surface hydration in CF models. 15-Lipoxygenase (LO) plays a central role in the "class switch" of eicosanoid mediator biosynthesis from leukotrienes to lipoxins, initiating the active resolution of inflammation. We hypothesised that defective eicosanoid mediator class switching contributes to the failure to resolve inflammation in CF lung disease. Using bronchoalveolar lavage (BAL) samples from 46 children with CF and 19 paediatric controls we demonstrate that the ratio of LXA4 to leukotriene B4 (LTB4) is depressed in CF BAL (p<0.01), even in the absence of infection (p<0.001). Furthermore, 15-LO2 transcripts were significantly less abundant in CF BAL samples (p<0.05). In control BAL, there were positive relationships between 15-LO2 transcript abundance and LXA4/LTB4 ratio (p=0.01, r=0.66) and with percentage macrophage composition of the BAL fluid (p<0.001, r=0.82), which were absent in CF. Impoverished 15-LO2 expression and depression of the LXA4/LTB4 ratio are observed in paediatric CF BAL. These observations provide mechanistic insights into the failure to resolve inflammation in the CF lung.


Subject(s)
Arachidonate 15-Lipoxygenase/metabolism , Cystic Fibrosis/blood , Leukotriene B4/chemistry , Lipoxins/chemistry , Anti-Bacterial Agents/therapeutic use , Bronchoalveolar Lavage Fluid/chemistry , Child , Child, Preschool , Cystic Fibrosis/metabolism , Cystic Fibrosis/physiopathology , Female , Humans , Inflammation , Leukotriene A4/chemistry , Longitudinal Studies , Lung/immunology , Lung/pathology , Lung Diseases/microbiology , Macrophages, Alveolar/metabolism , Male , Neutrophils/cytology , Neutrophils/metabolism
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